ResearchIn-Press PreviewImmunologyNeuroscience Open Access | 10.1172/jci.insight.177002
1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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1Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, United States of America
2Department of Psychology, Rutgers University, Piscataway, United States of America
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Published May 7, 2024 - More info
Astrocyte activation is a common feature of neurodegenerative diseases. However, the ways in which dying neurons influence the activity of astrocytes is poorly understood. Receptor interacting protein kinase-3 (RIPK3) signaling has recently been described as a key regulator of neuroinflammation, but whether this kinase mediates astrocytic responsiveness to neuronal death has not yet been studied. Here, we used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease to show that activation of astrocytic RIPK3 drives dopaminergic cell death and axon damage. Transcriptomic profiling revealed that astrocytic RIPK3 promoted gene expression associated with neuroinflammation and movement disorders, and this coincided with significant engagement of damage associated molecular pattern (DAMP) signaling. In mechanistic experiments, we show that factors released from dying neurons signal through receptor for advanced glycation endproducts (RAGE) to induce astrocytic RIPK3 signaling, which conferred inflammatory and neurotoxic functional activity. These findings highlight a mechanism of neuron-glia crosstalk in which neuronal death perpetuates further neurodegeneration by engaging inflammatory astrocyte activation via RIPK3.